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Mechanism of H-ras Oncogene Activation in Mouse Squamous Carcinoma Induced by an Alkylating Agent¹

New York University Medical Center, Institute of Environmental Medicine, New York, New York 10016

A mouse skin squamous cell carcinoma induced by topical application of the direct-acting alkylating agent ß-propiolactone contains an activated H-ras oncogene with an AT transversion at the second nucleotide of codon 61. The mutation was detected in NIH3T3 transfectant and original tumor DNA by an XbaI restriction enzyme polymorphism and confirmed by oligonucleotide "mismatch" hybridization. The mutation was not seen in the liver of the same animal. The activated oncogene also exhibited several restriction enzyme polymorphisms in transfectant DNA due to a reciprocal translocation 3' to the coding region of the gene, which occurred during transfection. The activating mutation was found in only 1 of 6 ß-propiolactone induced mouse skin tumors examined, the only tumor with a transforming H-ras oncogene. This is a much lower frequency of activation than that previously reported for the same tumor type induced by polycyclic aromatic hydrocarbons. The AT transversion mutation is consistent with a potentially direct mutagenic effect of a specific ß-propiolactone-DNA adduct.

¹ Supported by Grants CA36342, ES03563, and ES03847 and in part by Center Grants CA13343 and ES00260 from the NIH.

² To whom requests for reprints should be addressed, at NYU Medical Center, Institute of Environmental Medicine, 550 First Avenue, New York, NY 10016.

Received 5/11/87. Revised 10/22/87. Accepted 10/29/87.

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